DESCRIPTION (Applicant's abstract): This proposal will seek to further define the fundamental immunological and biochemical events that lead to pulmonary fibrosis. In animal models and humans with pulmonary fibrosis, monocyte recruitment and survival in the lung and activation of TGF-beta appear to be important components of the remodeling and fibrosis, however, the specific mechanisms involved have not been well elucidated. To address this issue, we found that in addition to promoting monocyte survival, macrophage colony-stimulating factor (M-CSF) also induces monocytes to release soluble factor(s) capable of activating latent TGF-beta. Since activation of TGF-beta appears to be casually associated with lung fibrosis, we will seek to identify the specific factor(s) released by M-CSF-stimulated monocytes that cleave latent TGF-beta and define the biochemical pathways responsible for stimulating the production of these factor(s). We will then focus on defining if active TGF-beta can facilitate monocyte survival directly or through inducing M-CSF release by fibroblasts. Finally, we will focus on "proof-of-concept" studies to define if monocyte proteases are critical in the activation of latent TGF-beta to assess the potential therapeutic application for agents that block these factors. The short-term goals of this proposal are to define the mechanisms by which monocyte recruitment and survival facilitate tissue remodeling and fibrosis. The long-term goal of this project is to better define the pathological events regulating the genesis of pulmonary fibrosis and to define novel targets to direct innovative therapies to suppress lung destruction and fibrosis associated with this devastating lung disease.